3-aminotricyclo [4.3.1.13.8] undecanes



United States Patent Office 3,397,233 Patented Aug. 13, 1968 ABSTRACT OFTHE DISCLOSURE 3-aminotricyclo[4.3.l.1 ]undecanes have the formula whereR is an amine radical which may be substituted by a carboXyl or acarboxylate. The compounds have the ability to inhibit and deter theincidence and growth of harmful viruses.

Background of the invention This invention relates to tricycloundecanes.More particularly, this invention refers to novel tricyclo[4.3.1.1undecanes having an amino or substituted amino group attached to a3-position tertiary or bridgehead nuclear carbon.

The need continues for effective antiviral agents useful for thetreatment of virus infections. I have now discovcred a novel class of3-amino and 3-substituted aminotricyclo[4.3.1.1 ]undecanes which showoutstanding properties in their ability to inhibit and deter incidenceand growth of a variety of harmful viruses.

Within the class of compounds of this invention an outstandingcombination of properties exists, as evidenced by standard tests in bothtissue culture and animals. Antiviral activity within this invention hasbeen observed against influenza A (strains WSN and swine), influenza A-2(strains Michigan A/AA and JPC) and parainfluenza (Sendai).

Summary of the invention The compounds of this invention have theformula:

where R1 R is N where n is 2, 3, 4, 5 or 6;

H N=G wherein R is hydrogen; alkyl of 1 through 6 carbon atoms;mono-substituted alkyl of 1 through 6 carbon atoms where the substituentis hydroxy, alkoxy of 1 through 2 carbon atoms, --NH NHR or NR R whereR; and R can be the same or diiferent and are alkyl radicals of 1through 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl;cyclobutylmethyl; R is R chlorine; bromine; formyl; CH;'COOH; -CH COOCHCH -COOC H with the proviso that when R, is an alkenyl or 'alkynylhaving the unsaturated bond in the l-position, R is alkyl ormono-substituted alkyl as defined above; and R is aliphatic;mono-substituted aliphatic where the substituent is aromatic orheterocyclic; aromatic; or heterocyclic containing not more than 12carbon atoms.

Detailed description of the invention Compounds hydrolyzable to thecompounds of formula 1 are for most purposes equivalent to thosecompounds and are of course contemplated as within the presentinvention.

It also will be understood that the compounds within the scope ofFormula 1 having a basic amino group, form salts, and such salts havinga nontoxic anion are also included within the scope .of the presentinvention. Representative of such salts are the hydrochlorides,hydrobromides, sulfates, phosphates, acetates, succinates, adipates,propionates, tartrates, citrates, bicarbonates, pamoates,cyclohexylsulfamates and acetylsalicylates. Of these the hydrochloridesand acetates and cyclohexylsulfamates are preferred, Thecyclohexylsulfamates have a pleasant taste and thus are particularlyuseful in preparing syrups for oral administration. Additionally, thecyclohexylsulfarnates have usefulness in making uncoated tablets fororal administration which have no objectionable bitter taste. Othersalts include those with caprochlorone and with penicillin.

The salts described above enhance the usefulness of the relativelyinsoluble amines in pharmaceutical applications.

Compounds of the above Formula 1 are preferred where the amine on theundecane moiety is substituted with dialkyl because of their outstandingcombination of unusual properties. While unsubstituted dialkyl is mostpreferred, some formulating advantages can be obtained using particularsubstituted products such as the hydroxy or alkoxy substituted compoundsas will be appreciated.

Lower alkyl substitutents such as the dimethyl and diethyl are mostpreferred. However, the monomethyl and monoethyl derivatives, as well asthe unsubstituted amino compounds, are preferred by comparison with mostof the substituted alkylamino derivatives.

Particularly preferred are the hydrochlorides of the followingcompounds:

3-aminotricyclo[4.3.1.l ]undecane 3-N-methylamin0tricyclo[4.3.1.1]undecane 3N-ethylaminotricyclo[4.3.1.1 ]undecane3-N,N-dimethylaminotricyclo[4.3.l.l ]undecane 3- (N-ethyl-N-methylaminotricyclo [4.3 .1 1 undecane 3-N,N-diethylaminotricyclo[4.3.1 1 undecaneThe above compounds can be prepared by a variety of methods.

The 3-aminotn'cyclo[4.3.l.1 ]undecane is readily prepared from the knowncompound 3-carboxytricyclo[4.3. 1.1 ]undecane by conversion of the acidto the acid chloride with thionyl chloride, followed by ammoniation tothe corresponding amide. The amide in turn is reacted with metallicsodium and bromine in methanol to giveS-carbomethoxyaminotricyclo[4.3.1.l ]undecane which is hydrolyzed underbasic conditions to obtain the desired 3-aminotricyclo[4.3.1.1]undecane.

This is basically the Hofmann procedure for converting a carboxylic acidto the corresponding amine. The acid can be reacted with methylchlorocarbonate and sodium azide, and the resulting acyl azidedecomposed by heating, to give the isocyanate which can be reacted withmethanol to give the methyl urethane, which is hydrolyzed to the aminewith alkali. This is an adaption of the Curtius reaction. These twomethods of obtaining 3-aminotricyclo[4.3.1.1 ]undecane are illustratedin Examples 1 and 2.

One or both of the hydrogens of the 3-amino nitrogen of3-aminotricyclo[4.3.1.1 ]undecane can be replaced by alkyl. This is mostconveniently done by acylation, for instance with an acyl halide, togive a 3-acylaminotricyclo[4.3.1.1 ]undecane, (which is then reduced to3-N-alkylaminotricyclo[4.3.1.1 ]undeoane. Lithium aluminum hydride isexcellent for this, although catalytic hydrogenation or any one of anumber of means of reduction can be used.

The 3-N-alkylaminotricyclo[4.3.1.1 ]undecanes can be acylated again andreduced to give the 3-N,N-dialkylamintricyclo[4.3.1.1 ]undecanes..Difrerent alkyl groups can be attached by this means. For instance,reduction of 3-acetamidotricyclo[4.3.1.1 ]undecane, followed by reactionof the product with butyryl chloride, followed by reduction gives the3-(N-butyl-N-ethylamino) compound. Of course, if acetyl chloride isused, the product is 3 (N,N diethylamino)t1icyclo[4.3.1.1 ]undecane,where the alkyl groups are alike.

Although formylation of the amino compound followed by reduction is apractical means of obtaining the N-methylamino compound, it may ifdesired also be obtained by reducing tricyclo[4.3.1.1 ]undecane-3-methylurethane, described in Example 3. Reduction of the 3-ethyl urethanegives the N-methylamino compound also.

The method of acylation and reduction is applicable to making compoundsin which the alkyl substituents are substituted. Acylation ofB-N-methylaminotricyclo [4.3.1.l ]undecane with 3-methoxypropionylchloride followed by reduction gives 3-[N-(3-methoxypropyD-N-methylaminoJtricyclo[4.3.l.1 ]undecane. Reaction of the amine ormonoalkyl amine with a dicarboxylic acid anhydride to give theN-substituted alkanamic acid, followed by reduction, introduces thehydroxyalkyl grouping. For instance, the reduction of N-[tricyclo[4.3.1.1 undecyl-(3)]-succinamic acid yields3-N-(4-hydroxybutyl)aminotricyclo[4.3.1.l ]undec ane.

Some substituted alkyl amino compounds are more easily made by otherroutes. Hydroxyethyland bishydroxyethyl compounds are made by reactionof the amine with ethylene oxide. N-carb-alkoxymethylamino compounds aremade by alkylation with alkyl chloroacetate and base. Aminoalkyl-,alkylaminoalkyl-, and dialkylaminoalkyl compounds are made by alkylationwith approproiate aminoalkyl halides and base.

In some cases, 3-N-alkylamino and dialkylaminotricyclo[4.3.1.1]undecanes are easily made by alkylation with alkylating reagents (suchas alkyl halides), without resorting to the method of acylation andreduction. When the reagents are used in molar amounts, themonoalkylamino compound is generally formed as the major product,whereas greater amounts of the reagents give the dialkylamino compound.This method is not as clearcut as the method of acylation and reduction,which is why it is less preferred. However, it sometimes becomes themethod of choice because it involves fewer steps.

Ethylene chloroand bromo-hydrin, and alkoxyalkyl halides can be used toalkylate the amino nitrogen, to give the hydroxyethyland*alkoxyalkylsubstitutions. For the reason just given, these reactionsare less preferable than the method of acylation and reduction, but maybe preferred in certain instances, and they illustrate an alternateroute to substituted-alkylaminotricyclo[4.3.1. 1 ]undecanes by ordinaryalkylation with a substituted alkylating reagent.

In preparing N-alkenyl, N,N-dialkenyl, N-alkynyl, and N,N dialkynyl 3aminotricyclo[4.3.1.1 ]undecanes, use of the appropriate alkenyl oralkynyl halide with an acid acceptor such as sodium bicarbonate in asolvent such as ethanol is the method of choice. Mixtures of the monoand di-alkenylated and -alkynylated compounds are produced, but theamount of the nudesired component can be minimized by varying the amountof the halide. With equimolar amounts of the amine and the halide themono substituted compounds predominate. With an excess of halide, thedisubstituted compounds predominate. In any event, the mono anddisubstituted compounds are relatively easy to separate, for example bydistillation. Of course, if the halide is present in huge excess, somequaternization will occur.

The method of acylation and reduction is quite applicable to preparingN-cyclopropylmethyl and N-cyclobutylmethyl compounds. Acylation of3-aminotricyclo [4.3.1.l ]undecane with cyclopropanecarboxylic acidchloride gives 3-(N-cyclopropylcarbonyl)aminotricyclo [4.3.1.1]undecane, which gives 3-N-cyclopropylmethylaminotricyclo[4.3. l.1]undecane on reduction.

To prepare N-cyclopropyl and N-cyclobutyl compounds, the known3-hydroxytricyclo[4.3.1.1 ]undecane is converted to 3 (ptoluenesulfonyloxy)tricyclo- [4.3.1.l ]undecane, for example withp-toluenesulfonyl chloride in pyridine, and this compound is heated inthe presence of cyclopropylamine or cyclobutylamine to yield 3 Ncyclopropylor 3 N cyclobutylaminotricyclo- [4.3.1.1 ]undecane byaminolysis. This method is also applicable to making N-[tricyclo[4.3.1.1]undecyl- (3)]alkyleneimines. Substitution of pyrrolidine for thecyclopropylamine yields N-[tricyclo[4.3.1.1 ]undecyl- (3) ]pyrrolidine.

Reaction of 3-aminotricyclo[4.3.1.1. ]undecane with aldehydes gives thecorresponding alkylidene, arylidene or heterocyclicylidenetricycloundecane. For instance, reaction of S-aminotricyclo[4.3.l.1.]undecane with formaledhyde gives N [tricyclo[4.3.l.1. ]undecyl-(3)]azomethine. Reaction of 3-aminotricyclo[4.3.1.1 undecane withbenzaldehyde gives 3-benzylideneaminotricyclo [4.3.1. 1 ]undecane.

Representative of the compounds of this invention are the followingcompounds and their salts:

3 -aminotricyclo[4.3.1.1 ]undecane 3 -N-methylaminotricyclo [4.3.1.1]undecane 3-N,N-dimethylaminotricyclo[4.3.l.1 ]undecane3-N-ethyl-N-methylaminotricyclo [4.3. l l undecane3-N,N-diethylaminotricyclo[4.3.1.1 ]undecane 7N-chloro-N-methyl-3-aminotricyclo[4.3.1.1

undecane N-chloro-N-hexyl-3-aminotricyclo[4.3.1.1

undecane N-bromo-3 -aminotricyclo [4.3. 1.1 ]undecaneN-bromo-N-methyl-3-aminotricyclo[4.3.1.1

undecane N-bromo-N-hexyl-3-aminotricyc1o[4.3.1.1

undecane 3 -formamidotricyclo[4.3.1.1 ]undecane3-N-methylformamidotricyclo[4.3.1.1 ]undecane3-N-hexylformamidotricyclo[4.3.1.1 ]undecane N- [tricyclo [4.3. 1 1undecyl-(3 glycine N-[tricyclo [4.3.1.1 sarcosine N- [tricyclo [4.3 l 1undecyl-( 3 ]-N-hexyl glycine N- [tricyclo [4.3 .1 1 undecyl- 3-Nhexylglycine,

;methyl ester N-[tricyclo[4.3.1.1 ]undecy1-(3 ]sarcosine, ethyl esterN-[tricyclo [4.3.1.1 ]undecyl-(3 glycine, ethyl ester N- [tricyclo [4.3.l 1 undecyl- 3 N-hexylglycine,

ethyl ester N-[tricyclo[4.3.1.1 ]undecyl-(3) ]azomethine3-benzylideneaminotricyclo[4.3.1.1 ]undecane 3-ethylideneaminotricyclo[4.3 1.1 undecane 3-isohexylideneaminotricyclo [4.3.1. l ]undecane 3-naphthylideneaminotricyclo [4.3 1 1 1 undecane3-furfurylideneaminotricyclo[4.3 .1.1 ]undecane N-[tricyclo [4.3. 1.1undecyl-( 3 Jaziridine N- [tricyclo[4.3.1. 1 undecyl- (3 azetidineN-[tricyclo[4.3.1.1 undecyl-(3 lpyrrolidine N-[tricyclo[4.3.1.1]undecyl-(3) ]piperidine N- [tricyclo [4.3 1 1 undecyl- (3 )-lhexamethyleneimine This invention will be better understood by referenceto the following illustrative examples, which are given in addition tothose above. Parts and percentages are by weight unless otherwiseindicated.

EXAMPLE 1 3-carboxytricyclo[4.3.1.1 ]undecane is prepared according toStetter, Schwarz, and Hirschhorn, Ben, 92, 1634 (1959), froml-hydroxymethyl adamantane. The acid is converted to the acid chlorideby refluxing with excess thionyl chloride. The excess reagent isremoved, under reduced pressure, and the crude acid chloride is droppedslowly into concentrated ammonia at 5 C. The resultant amide isrecrystallized from acetone-water to give a white crystalline solid,M.P. 180-181 C., in 90% yield. The amide, 8 parts, is added to asolution of 2.1 parts of metallic sodium in 175 parts of methanol, thesolution is cooled to 0 C., and 8 parts of liquid bromine is droppedinto the well-stirred solution. Stirring is continued for minutes at 0,then for 15 minutes at 55, and finally for 30 minutes at the boilingpoint. The methanol is removed by distillation and the residue isrecrystallized from dilute acetone. The product is a white crystallinesolid, 10 parts or 97% yield, of 3-carbomethoxyaminotricyclo[4.3.1.1]undecane. This is hydrolyzed by refluxing with excess powdered sodiumhydroxide in diethylene glycol for 16 hours. A large excess of water isadded and the 3-aminotricyclo[4.3.1.1 ]undecane is extracted from thereaction mixture with chloroform. This solvent is removed, replaced bycyclohexane and dry hydrogen chloride is passed into the solution. Theprecipitated amine hydrochloride is removed by filtration, dissolved inwater, and the free amine is regenerated by making the solution stronglyalkaline. This is taken up in chloroform, the solvent is removed, andthe free amine is sublimed at 0.2 mm. pressure. The sublimate is pureS-aminotricyclo [4.3.1.1 ]undecane, M.P. 206206.5 C., in a sealedcapillary.

Analysis.Calcd. for C H N: C, 79.94; H, 11.59; N, 8.48. Found: C, 81.68;H, 11.72; N, 8.59. N.E. Calcd.: 165.27. Found: 176.

The infrared spectrum and the NMR spectrum are consistent with thoseexpected for this compound.

EXAMPLE 2 3 carboxytricyclo[4.3.1.1 ]undercane, 30 grams (0.1545 mole)is dissolved in 200 milliliters of acetone and a solution of 12.7 grams(0.16 mole) of pyridine in 25 milliliters of acetone is added slowly.The reaction mixture is cooled at 3 C. and a solution of 16 grams (0.17mole) of methyl chlorocarbonate in 25 milliliters of acetone is addedslowly while holding the temperature below 5 C. The mixture is stirredfor one hour and a solution of 11.8 grams (0.18 mole) of sodium azide in30 milliliters of water is added slowly. After complete addition thereaction mixture is stirred for 16 hours at room temperature, dilutedwith 4 volumes of water and extracted with toluene. The toluene extractis washed with water, 1% solution hydroxide, 1% hydrochloric acid andthen with water. The toluene solution is then dried with calciumchloride and heated at C. until no more nitrogen is evolved from theacyl azide. The toluene is removed under reduced pressure and theresidue is refluxed for 16 hours with methanol. Removal of the methanolleaves a solid residue, 26.16 grams, 76% conversion to tricyclo[4.3.l.l]undecane-3-methyl urethane. After recrystallization from acetone-water,this melts at 104- 106 C. Alkaline hydrolysis gives 3 aminotricyclo-[4.3.1.1 ]undecane.

EXAMPLE 3 A solution of 20.5 grams (0.092 mole) of tricyclo- [4.3.1.1]undecane-3-methyl urethane, prepared as in Example 2, in 100milliliters of dry diethyl ether is added slowly to a suspension of 5.65grams of lithium aluminum hydride in 100 milliliters of dry ether. Aftercomplete addition, the reaction mixture is refluxed for one hour, theether is removed by distillation, the residue is made strongly alkalinewith sodium hydroxide and the product is isolated by steam distillation.The steam distillate is extracted with ether, the extract is dried withsolid KOI-I, filtered, and dry HCl is passed into the solution. Theamine hydrochloride which forms crystallizes out of the etherealsolution and is removed by filtration. After recrystallization fromethyl acetate, the melting point is 225-226 C. The yield is 6.8 grams,34% of theory, of 3 N methylaminotricyclo[4.3.1.1 ]undecanehydrochloride.

Analysis.Calcd. for C H NCl: N, 6.52; C], 16.45. Found: N, 6.41; Cl,15.98.

EXAMPLE 4 A 10.35 gram sample (0.05 mole) of 3-acetamidotr1cyclo[4.3.l.1]undecane prepared by acetylation of the corresponding amine with aceticanhydride containing a drop of sulfuric acid is dissolved in 200milliliters of dry tetrahydrofuran and added to a suspension of 3.0grams of lithium aluminum hydride in 350 milliliters of dry ether. Aftercomplete addition, the mixture is refluxed for one hour and the solventis distilled from the reaction vessel. Steam is then passed in until aclear distillate results. The distillate is then extracted with etherand the extract is dried with solid sodium hydroxide. Dry hydrogenchloride is then passed into the filtered solution and the precipitatedamine hydrochloride is removed by filtration and recrystallized to yield3-N-ethylaminotricyclo[4.3.1.1 ]undecane hydrochloride.

EXAMPLE 5 Molar equivalents of 3-aminotricyclo[4.3.1.1 ]undecane andcaproyl chloride are reacted in pyridine solution to give 3 Ncaproylaminotricyclo[4.3.1.1 ]undecane, which is isolated by pouring thereaction mixture into water and removing the crystalline amide byfiltration. After careful drying of the product, a tetrahydrofuransolution is added slowly to a suspension of one molar equivalent (25%excess) of lithium aluminum hydride in diethyl ether. After completeaddition, the reaction mixture is refluxed for 2 hours, the solvent isdistilled and the amine is steam distilled until the distillate isclear. The product is extracted with ether and the ethereal solution isdried over solid sodium hydroxide. Dry hydrogen chloride is passed intothe ethereal solution. Evaporation of the ether gives3-N-hexylaminotricyclo[4.3.1.1 undecane, hydrochloride.

EXAMPLE 6 A 50-milliliter round-bottom flask is charged with 6.90 grams(0.15 mole) of 98% formic acid and 12.1 grams (0.15 mole) of 37%formalin solution. Then 8.26 grams (0.05 mole) of3-aminotricyclo[4.3.l.1 ]undecane is charged, a condenser is attached,and the mixture is heated at 95 C. on the steam bath for 16 hours. Gasis evolved during the heat-up period and for some time thereafter. Aftercooling, the mixture is transferred to a separatory funnel with 50milliliters of water, 25 milliliters of 50% sodium hydroxide is added,and the mixture is extracted with three ZS-milliliter portions of ether.The ether extracts are combined, washed with 50 milliliters of 12.5%sodium hydroxide, dried with potassium hydroxide pellets, andconcentrated in a vacuum to yield 3-N,N-dimethylarninotricyclo [4.3. 1.1undecane.

EXAMPLE 7 The 3 -N-methylaminotricyclo [4. 3 1 1 undecane prepared inExample 3 is converted to the acetyl derivative by gently warming thecompound with a slight excess of acetic anhydride containing a drop ofsulfuric acid. The resulting solution is poured on ice and extractedwith chloroform. Removal of the chloroform yields 3-N-methylacetaminotricyclo[4.3.1.l ]undecane which is purified bydistillation. A solution of the amide in tetrahydrofuran is added slowlyto a suspension of one molar equivalent of lithium aluminum hydride indiethyl ether. After complete addition, the reaction mixture is refluxedfor 4 hours, the solvent removed and the amine isolated by steamdistillation. The steam distillate is extracted with ether and theextract is dried with solid sodium hydroxide. The dry ethereal solutionis saturated with hydrogen chloride and after removal of the ether, thehydrochloride of 3-(N-methyl N ethylamino)tricyclo- [4.3.1.1 ]undecaneis obtained.

EXAMPLE 8 Example 5 is repeated, substituting equivalent amounts ofcyclopropanecarboxylic acid chloride for the caproyl chloride, to obtain3 N cyclopropylcarbonylaminotricyclo[4.3.1.l ]undecane which is thenreduced with lithium aluminum hydride to 3 Ncyclopropylmethylaminotricyclo[4.3.1.1 ]undecane.

EXAMPLE 9 A 100 milliliter flask with a stirrer and reflux condenser ischarged with 0.1 mole of 3-aminotricyclo[4.3.1.1 undecane, 0.1 mole ofethyl chloroacetate, 0.11 mole of sodium bicarbonate and 40 millilitersof methanol. The mixture is refluxed overnight, the insoluble materialis removed by filtration and the solution is evaporated to dryness. Theresidue is dissolved in 1 Normal hydrochloric acid, regenerated by 5%sodium hydroxide, and extracted with ether. The ether solution is driedover anhydrous sodium sulfate and the solvent is removed. The residue issubjected to vacuum distillation at 0.1 mm. and divided into a lowerboiling fraction, which is recovered starting material, and a higherboiling fraction, which is N-[tricyclo[4.3.1.l ]undecyl-(3)] glycineethyl ester.

EXAMPLE 10 Equimolar quantities of freshly prepared Z-diethylaminoethylchloride and 3 N methylamin0tricyclo- [4.3.1.1 ]undecane and 10% excessof sodium bicarbonate are refluxed in methyl alcoholic solution for 16hours. The reaction mixture is poured into Water and extracted withether. The ether extract is dried with solid sodium hydroxide and thesolvent is removed. The residue is 3-N-(Z-diethylaminoethyl) Nmethylaminotricyclo- [4.3.1.l ]undecane.

EXAMPLE 1 l A 2-liter 4-necked round-bottom flask is equipped withthermometer, dropping funnel, reflux condenser, paddle stirrer and aconnection to a gas meter, and charged with 500 ml. of absolute ethanol,50.4 g. (0.60 mole) of sodium bicarbonate and 40.3 g. (0.20 mole of3-aminotricyclo[4.3.1.1 ]undecane hydrochloride. Then, 24.2 g. (0.20mole) of allyl bromide is added from the dropping funnel. There is noappreciable evolution of carbon dioxide. The mixture is gradually warmedto 65 C., whereupon gas evolution begins. The reaction is allowed toproceed until no more gas is evolved (about 11.5 liters). The mixture iscooled, the solids are filtered, and the filtrate is evaporated. Theresidue is distributed between ether and 10% sodium hydroxide solution.The ether layer is dried with anhydrous potassium carbonate andevaporated to give an oil. This is distilled at reduced pressure to givetwo main fractions. The lower-boiling fraction is 3 Nallylaminotricyclo[4.3.l.1 ]undecane. The higher is3-N,N-diallylaminotricyclo[4.3.l.1 ]undecane.

EXAMPLE 12 A Z-liter 4-necked round-bottom flask is equipped withthermometer, dropping funnel, reflux condenser, paddle stirrer and aconnection to a gas meter. It is charged with 500 ml. of abs. ethanol,50.4 g. (0.60 mole) of sodium bicarbonate and 43.0 g. (0.20 mole) of3-N-methylaminotricyclo[4.3.l.1 ]undecane hydrochloride. Then, 24.2 g.(0.20 mole) of allyl bromide is added from the dropping funnel. Themixture is gradually warmed to 65 (3., when gas evolution begins. Thereaction is allowed to proceed until no more gas is evolved (ca. 11.5lite-rs). It is cooled, the solids are filtered, and the filtrate isevaporated. The residue is distributed between ether and 10% sodiumhydroxide solution. The ether layer is dried with anhydrous potassiumcarbonate and evaporated to give a residue of 3 N allyl Nmethylaminotricyclo- [4.3.1.1 ]undecane.

EXAMPLE 13 A reaction is run as described in Example 12, using 40.3 g.(0.20 mole) of S-aminotricyclo[4.3.1.l ]undecane, 16.4 g. (0.20 mole) ofpropargyl chloride, 50.4 g. (0.60 mole) of sodium bicarbonate and 500ml. of absolute ethanol. The cooled mixture is filtered and the filtrateis evaporated. The residue is distributed between 10% sodium hydroxideand ether. The ether layer is dried with anhydrous potassium carbonateand evaporated. The residue is distilled at reduced pressure to yieldtwo main fractions. The lower-boiling fraction is3-N-propargylaminotricyclo[4.3.1.1 ]undecane and the higher is 3-N,N-dipropargylaminotricyclo [4.3.1.1 ]undecane.

EXAMPLE 14 A flask equipped with a Dean-Stark water separator is chargedwith 0.1 mole of 3-aminotricyclo[4.3.1.l ]undecane and 0.1 mole offreshly distilled benzaldehyde in 50 milliliters of toluene. Thereaction mixture is refluxed for 45 hours, the toluene evaporated andthe residue recrystallized to give 3 -benzaldiminotricyclo [4.3.l.1]undecane.

EXAMPLE 15 The organic layer of 3-N-hydroxymethylaminotricyclo [4.3.1.l]undecane or obtained in accordance with Example 19 hereinafter, isdistilled at reduced pressure to yield N-[tricyclo[4.3.l.l ]undecyl-(3)]azomethine.

EXAMPLE 16 A 3-neck l-liter flask fitted with a stirrer and athermometer is charged with 250 milliliters of 98% sulfuric acid whichis then cooled to C. A mixture of grams of solid1-hydroxymethyladamantane and 9 grams of sodium cyanide (3 molarequivalents) is added in small portions, with good stirring, to theacid, controlling the temperature of the reaction mixture between 20 C.by ice-bath cooling. When addition is complete, the reaction is allowedto warm slowly to room temperature. An exothermic reaction occurs but iscontrolled by the ice bath so that the temperature of the reaction massdoes not exceed 50 C. The reaction mixture is stirred for 2 hours andpoured on ice. The acidic solution is neutralized with ammoniumhydroxide and the organic material isolated by extraction withchloroform. Evaporation of the chloroform yields3-formamidotricyclo[4.3.l.1 ]undecane mixed withl-formamidomethyladamantane. The desired product, 3-formamid0tricyclo[4.3 1 l lundecane, can if desired be separated from the by-product byextraction of the mixture with cold excess cyclohexane in which it isinsoluble. The melting point is l58l60 C. after crystallization fromethyl acetate.

This compound can also be made as follows:

An 0.05 mole amount of 3-aminotricyclo[4.3.l.1 undecane is refluxed 19hours in 25 ml. of butyl formate. The excess butyl formate is removed byvacuum concentration, and the residue is recrystallized to yield3-formamidotricyclo[4.3.1.1 ]undecane.

EXAMPLE 17 A solution of 0.1 mole of 3-aminotricyclo[4.3.1.1 undecane in50 milliliters of benzene is added slowly to a solution of 0.1 mole ofsuccinic anhydride in 100 milliliters of benzene. The mixture is thenheated under reflux for one hour and the benzene removed bydistillation. An

.excess of acetyl chloride, 0.15 mole, is added to the residue and themixture heated under reflux on a steam bath for one hour. The excessacetyl chloride is distilled off at atmospheric pressure and the aceticacid formed by dehydration of the initially formed succinamic acid isremoved at 100 C. under 15 mm. pressure. The residue is nearly pure3-N-tricyclo[4.3.1.l ]undecylsuccinimide. The crude product, afterdrying in a vacuum desiccator over solid sodium hydroxide pellets, isdissolved in dry tetrahydrofurane and added slowly to a suspension of0.15 mole, an excess of lithium aluminum hydride in diethyl ether. Aftercomplete addition, the reaction mixture is refluxed for 2 hours, thesolvent removed by distillation, and the amine isolated by steamdistillation. The steam distillate is extracted with ether, the solutiondried with sodium hydroxide, and dry hydrogen passed into the filteredsolution until no more is absorbed. Evaporation of the ether yieldsN-[tricyclo[4.3.l.1 ]undecyl- (3) ]pyrrolidine hydrochloride.

EXAMPLE 18 Example 5 is repeated, substituting equivalent amounts of3-methoxypropionyl chloride for the caproyl chloride, to obtain3-(N-methyl-3-methoxypropionamido)tricyclo 12 [4.3.l.1 ]undecane whichis then reduced with lithium aluminum hydride to3-N-(3-methoxypropyl)-N-methylaminotricyclo[4.3.1.l ]undecane.

EXAMPLE 19 A suitable flask equipped with stirrer, thermometer, refluxcondenser, dropping funnel and cooling bath is charged with 2.0 moles of3-aminotricyclo[4.3.1.1 undecane. A 37% aqueous solution of formaldehyde(2.05 moles) is added slowly with stirring, maintaining the temperaturebelow 40 C. After addition is complete, the reaction is cooled to roomtemperature, and powdered potassium hydroxide (10 g.) is added to aid inseparation of the water. The organic layer is separated and dried overpotassium hydroxide to yield 3-N-hydroxymethylaminotricyclo[4.3.1.l]undecane.

EXAMPLE 20 Example 19 is repeated using 2.0 moles of 3-N-methylaminotricyclo[4.3.1.l ]undecane is place of the 2.0 moles of3-aminotricyclo[4.3.1.l ]undecane. The product is 3 -N-hydroxymethylN-methylaminotricyclo [4.3.1.1 ]undecane.

EXAMPLE 21 A 0.1 mole amount of3-N-hydroxymethyl-N-methylaminotricyclo[4.3.l.1 ]undecane (Example 20)is refluxed at 55 C. in a mixture of ml. of anhydrous diethylamine and10 g. of potassium hydroxide pellets for 4 hours. The mixture is cooledand the liquid is decanted from the residual pellets and the small layerof concentrated potassium hydroxide solution. It is distilled at reducedpressure to yield 3N-diethyaminomethyl-N-methylaminotricyclo[4.3.l.1]undecane.

EXAMPLE 22 A solution of 0.5 mole of 3-aminotricyclo[4.3.1.1 undecane inmilliliters of tetrahydrofuran and 30 milliliters of water is chargedinto a 400 milliliter stainless steel autoclave, and 5.0 grams (0.11mole) of ethylene oxide is injected. The autoclave is heated to 70 C.for 24 hours after which time it is cooled and cautiously vented.Solvent is removed at reduced pressure, and the residue is extractedwith ether. The ether extract is dried With anhydrous potassiumcarbonate. Solvent is removed at reduced pressure and the residue issubjected to sublimation at 100 C./20 mm. in order to remove unreacted3-aminotricyclo[4.3.l.l ]undecane. The residue from the sublimation isdistilled under vacuum to yield 3 N(2-hydroxymethyl)aminotricyclo[4.3.1.1 undecane. Continuation of thedistillation gives 3-N,N-di(2-hydroxyethyl)aminotricyclo [4.3.1.1undecane as a higherboiling fraction.

EXAMPLE 23 A suspension of 0.1 mole of 3-aminotricyclo[4.3.1.1 undecanein 100 milliliters of ice water is placed in 500- milliliter flaskequipped with mechanical stirrer and thermometer. The flask is cooled inan ice bath and 142 grams of 5.25% sodium hypochlorite solution(commercial Clorox) is added at such a rate that the temperature doesnot exceed 10 C.

After the addition is complete the ice bath is removed and the mixtureis stirred for 30 minutes. It is then extracted with three SO-milliliterportions of ether. The combined ether extracts are dried over calciumchloride. The solution is filtered and solvent is removed under vacuumto yield 3 N chloroaminotricyclo [4.3.1.1 undecane.

EXAMPLE 24 A mixture of 0.10 mole of 3-aminotricyclo[4.3.1.1 undecaneand 9.87 grams (0.10 mole of 38% hydrochloric acid in 100 milliliters ofwater is concentrated in vacuo at 60 C. The resulting salt,3-aminotricyclo- [4.3.l.l ]undecane hydrochloride, is dried in vacuo at60 C.

14 0.5% by weight based on the total weight of the composition and notmore than 90% by weight.

Besides the active ingredient of Formula 1 the antiviral compositionwill contain a solid or liquid nontoxic EXAMPLES 25-37 Example 24 isrepeated substituting the following indicated reactants for those ofthat example to obtain the indicated product:

pharmaceutical carrier for the active ingredient.

Ex. Product of Example Acid Product as 1, 0.10 mole 48% hydrobromic acid(0.10 mole) 3-aminotricyclo[4.3.1.1 undecane,

hydrobromide.

26 3, Free Amine, 0.10 mole 85% phosphoric acid (0.33 mole)3-N-methylaminotricyc1o[43.1.1 1-

undecane, phosphate.

27 5, Free Amine, 0.10 mole Sulfuric acid (0.050 mole)3-N-hoxylaminotricyclo[4.3.1.1 1-

undecane, sulfate. 28 7, Free Amine, 0.10 mole Tartaric acid (0.10 mole)3-N-methyl-N-ethylaminotricyclo- [4.3.1.l ]undecane, bitartrate.

29 4, Free Amine, 0.10 mole Tartaric acid (0.050 mole)3-N-ethylaminotricyelo[4.3.1.1

undecane, tartrate.

3, Free Amine, 0.10 mole Maleic acid (0.050 mole)3-N-rnethylaminotrieyclo[4.3.1.1

undecane, maleate.

31 18, 0.10 mole Perchloric acid (0.10 mole)3N-(8methoxypropyl)-N-methylaminotricyc1o[4.3.1.1 ]undecane,perchlorate.

32 17, Free Amine, 0.10 mole"--- Acetic acid (0.10 mole)N-[tricyclo[4.3.1.1 ]undecyl-(3)lpyrrolidine, acetate. 33 9, 0.10 moleCitric acid (0.033 mole) 3-(N-carboethoxyrnethylamino)tricyclo[4.3.1.1Hundecane, citrate.

34 10, 0.10 mole Citric acld (0.10 mole) 3-N-(2-(1iethylaminoethyl)-N-methylarnino-tricyclo[4.3.1.1 undecane, dihydrogen citrate.

35 22, 0.10 mole Succinic acid (0.050 mole)3-N-(2-hydroxyethyl)aminotricyclo- [4.3.1.1 ]undecane, succinate.

36 2, 0.10 mole Mandelic acid (0.10 mole) 3aminotricyclo[4.3.1.1]undecane,

. mandelate.

37 1, 0.10 mole Lactic acid, 0.10 mole 3-aminotricyclo[4.3.1.l]undecane,

lactate.

EXAMPLE 38 In one embodiment of a pharmaceutical composition of Asolution of 0.20 mole of 3-aminotricyclo[4.3.1.1 undecane hydrochloridein 100 milliliters of water is added to a solution of 0.10 mole ofpamoic acid disodium salt [4,4-methylenebis(3-hydroxy-2-naphthoic acid)disodium salt] in 500 milliliters of water. The resulting precipitate isfiltered, washed well with water, and dried in vacuo to give3-aminotricyclo[4.3.1.1 ]undecane pamoate.

The preceding examples can be repeated substituting equivalent amountsof appropriate starting materials to obtain other compounds of thisinvention including those listed hereinbefore.

The compounds of Formula 1 above can be administered in the antiviraltreatment according to this invention by any means that effects contactof the active ingredient compound with the site of virus infection inthe body. It will be understood that this includes the site prior toinfection setting in as well as after. For example, administration canbe parenterally, that is subcutaneously, intravenously, intramuscularly,or intraperitoneally. Alternatively or concurrently, the compounds areeffective on administration by the oral route. Since particularlyeffective against respiratory infections such as viral pneumonia,administration can be by vapor or spray through the mouth or nasalpassages.

The compounds within the scope of this invention are valuable for viralprophylaxis, as well as for therapeutic treatment.

The dosage administered will be dependent upon the virus being treated,the age, health and weight of the recipient, the extent of infection,kind of concurrent treatment if any, frequency of treatment and thenature of the effect desired. Generally a daily dosage of activeingredient compound will be from about 1 to 50 milligrams per kilogramof body weight, although lower, such as 0.5 milligram per kilogram, orhigher amounts can be used. Ordinarily, from 1 to and preferably 1 to 10milligrams per kilogram per day, in one or more applications per day, iseffective to obtain the desired result.

The active ingredient of Formula 1 can be employed in usefulcompositions according to the present invention in such dosage forms astablets, capsules, powder packets or liquid solutions, suspensions, orelixirs, for oral administration, or liquid solutions for parenteraluse, and in certain cases, suspensions for parenteral use (exceptintravenous). In such compositions the active ingredient will ordinarilyalways be present in an amount of at least this invention, the solidcarrier is a capsule which can be of the ordinary gelatin type. In thecapsule will be from about 30-60% by weight of a compound of Formula 1or 2 and 7040% of a carrier. In another embodiment the active ingredientis tableted with or without adjuvants. In yet another embodiment, theactive ingredient is put into powder packets and employed. Thesecapsules, tablets and powders will generally constitute from about 5% toabout and preferably from 25% to 90% by weight. These dosage formspreferably contain from about 5 to about 500 milligrams of activeingredient, with from about 25 to about 250 most preferred.

The pharmaceutical carrier can, as previously indicated, be a sterileliquid such as water and oils, including those of petroleum, animal,vegetable, or synthetic origin, for example peanut oil, soybean oil,mineral oil, seasame oil and the like. In general, Water, saline andaqueous dextrose (glucose) and related sugar solutions and glycols suchas propylene glycol or polyethylene glycol are preferred liquidcarriers, particularly for injectible solutions. Sterile injectiblesolutions will ordinarily contain from about 0.5 to 25%, and preferablyabout 1 to 10% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient ordinarily will constitute fromabout 0.5 to 10%, and preferably about 2 to 5%, by weight. Thepharmaceutical carrier in such compositions can be a watery vehicle suchas an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Remingtons Practice ofPharmacy by E. W. Martin and E. F. Cook, a well known reference text inthis field.

In addition to the exemplary illustrations above, the following examplesfurther explain the present invention:

EXAMPLE 39 A large number of unit capsules are prepared by fillingstandard two-piece hard gelatin capsules weighing about 50 milligramseach with 50 milligrams of powdered 3- aminotricyclo[4.3.1.l ]undecanehydrochloride; milligrams of lactose and 1 milligram of Cab-O-Sil.

15 EXAMPLE 40 Example 39 is repeated except that soft gelatin capsulesare used and the powdered 3-aminotricyclo[4.3.1.1 un decanehydrochloride is first dissolved in mineral oil.

EXAMPLE 41 Example 39 is repeated except that the dosage unit is 50milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligramsof magnesium stearate and 100 milligrams of lactose, mixed and for-medinto a tablet by a conventional ta'bleting machine. Slow release pillsor tablets can also be used, by applying appropriate coatings such assugar-base coatings well known to the art.

EXAMPLE 42 A parenteral composition suitable for administration byinjection is prepared by stirring 5% by weight of the active ingredientof Example 39 in sterile aqueous 0.9% saline.

A large variety of compositions according to this invention can thusreadily be made by substituting other compounds of this invention, andincluding specifically but not limited to compounds of this inventionthat have specifically been named hereinbefore. The compounds will beused in the amounts indicated in accordance with procedures well knownand described in the Martin and Cook text mentioned above.

The compounds of this invention are particularly effective against swineinfluenza. An important embodiment of this invention therefore is thecontrol of this infection by incorporating an active ingredient compoundin the diet of the affected animal. For most purposes, an amount ofactive compound will be used to provide from about 0.0001 to 0.1% byweight of the active compound based on the total weight of feed intake.Preferably, from 0.001% to 0.02% by weight will be used.

In a related aspect, novel and useful compositions are provided by thisinvention which comprise at least one active ingredient compound withinthe scope of this invention in admixture with an animal feed.Descriptions of suitable feeds can be found in the book Feeds andFeeding by Frank B. Morrison, published by the Morrison PublishingCompany of Ithaca, N.Y., 1948, 21st edition. The selection of theparticular feed is within the knowledge of the art and will depend ofcourse on the animal, the economics, natural materials available, thesurrounding circumstances and the nature of the effect desired, as willbe readily understood.

Particularly important composition according to this feature of theinvention is a concentrate, suitable for preparation and sale to afarmer or livestock grower for addition to the animals feedstufls inappropriate proportion. These concentrates ordinarily comprise about0.5% to about 95% by weight of the active ingredient compound togetherwith a finely divided solid, preferably flours, such as wheat, corn,soya bean and cottonseed. depending on the recipient animal, the solidadjuvant can be ground cereal, charcoal, fullers earth, oyster shell andthe like. Finely divided attapulgite and bentonite can be used, theselatter materials also acting as solid dispersing agents.

The feed compositions, as well as the just described concentrates, canadditionally contain other components of feed concentrates or animalfeeds, as will be readily understood. Other particularly importantadditives include proteins, carbohydrates, fats, vitamins, minerals,antibiotics, etc.

The following example will further illustrate this aspect of thisinvention,

16 EXAMPLE 43 A feed for pigs is prepared as follows:

Pounds Oat groats 350 Yellow corn, ground 1000 Molasses Soybean meal 450Dried skim milk 100 Ground limestone 20 Dicalcium phosphate 20 Salt plustrace mineral mix 10 Standard vitamin premix 1 According to thisinvention there is added to the pigs diet a concentrate of 50% of3-N-methylaminotricyclo [4.3.1.1 ]undecane hydrochloride as the activeingredient and 50% by weight corn flour, in an amount that pro vides0.015% by weight of the active ingredient based on the total diet.

The above and similar examples can be carried out in accordance with theteachings of this invention, as will be readily understood by personsskilled in the art, by substitution of components and amounts in placeof those specified. Thus, the foregoing detailed description has beengiven for clearness of understanding only and no unnecessary limitationsare to be understood therefrom.

I claim:

1. A compound selected from the group consisting of those of theformula:

where R is selected from the group consisting of /Rt -N and where n isan integer of 2 through 6; wherein:

R is selected from the group consisting of hydrogen; alkyl of 1 through6 carbon atoms; mono-substituted alkyl of 1 through 6 carbon atoms wherethe substituent is hydroxy, alkoxy of 1 through 2 carbon atoms, NH -NHRand NR R where R and R are each alkyl of 1 to 4 carbon atoms; alkenyl of2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms;cyclopropyl; cyclobutyl; cyclopropylmethyl; and cyclobutylmethyl; and

R is selected from the group consisting of R chlorine and bromine; withthe proviso that when R is selected from the group consisting of alkenylor alkynyl having the unsaturated bond in the l-position, R is selectedfrom the group consisting of alkyl of 1 through 6 carbon atoms andmono-substituted alkyl of 1 through 6 carbon atoms where the substituentis selected from the group consisting of hydroxy, alkoxy of 1 through 2carbon atoms, NH NHR and -NR R where R; and R are each alkyl radicals of1 through 4 carbon atoms;

and nontoxic salts of said compound.

2. A compound of the formula NR 1R2 17 18 wherein R and R are each analkyl group of from 8. 3-N,N-diethy1aminotricyclo[4.3.1.1 ]undecane. 1to 6 carbon atoms.

3. 3-aminotricyclo[4.3.1.1 ]undecane. N0 feferencfis 4.3-N-methy1a1ninotricyc1o[4.3.1.1 ]undecane. 5.3-N-ethy1aminotricyclo[4.3.1.1 ]undecane. 5 CHARLES PARKER: Pnmmy Examme6. 3-N,N-dimethy1aminotricyclo[4.3.1.1 ]undecane. P, C, IVES AssistantExaminer.

7. 3 (N-ethy1 N methylamino)tricycl0[4.3.1.1 undecane.

